Drug Development Division, Dainippon Sumitomo Pharma Co., Ltd, Osaka, Japan.
J Infect Chemother. 2011 Dec;17(6):831-41. doi: 10.1007/s10156-011-0271-9. Epub 2011 Jul 20.
The objectives of this study were to develop a population pharmacokinetic (PK) model of meropenem, to simulate the percent time above minimum inhibitory concentration (%T > MIC) at various MICs, and to estimate effective dosage regimens by calculating the target attainment rates against various strains of bacteria. A total of 209 plasma samples (1-3 concentrations per patient) were obtained from 98 adult Japanese patients with febrile neutropenia in an open-labeled Phase 3 study. The final population PK model was fit to a two-compartment model with zero-order input. Creatinine clearance had a positive significant correlation with CL. Gender had a significant effect on Vc; however, this effect was small, and the PK profile in male patients was similar to that in female patients. The population PK parameters developed in this study are useful in simulating PK profiles of meropenem at various dosage regimens precisely for calculation of %T > MIC. The PK-PD analysis indicated that 0.5 g every 6 h (q6h) was more effective than 1 g q12h, although provided 2 g per day in total. A meropenem dosage regimen of 1 g q8h and/or longer infusion duration was better against a pathogen of comparatively low sensitivity, Pseudomonas aeruginosa (for MIC ≥2 μg/ml). Although causative bacteria were identified in a small number of patients, the target attainment rates at 75%T > MIC (89%) were comparable to microbiological response (89%). The present PK-PD analyses under various conditions are useful in the treatment of febrile neutropenia.
本研究的目的是建立美罗培南的群体药代动力学（PK）模型，模拟不同 MIC 时最小抑菌浓度（MIC）以上时间的百分比（%T > MIC），并通过计算针对各种细菌株的达标率来估计有效剂量方案。在一项开放标签的 3 期研究中，共从 98 例发热性中性粒细胞减少症的日本成年患者中获得了 209 份血浆样本（每位患者 1-3 个浓度）。最终的群体 PK 模型适合零级输入的两室模型。肌酐清除率与 CL 呈正显著相关。性别对 Vc 有显著影响；然而，这种影响很小，男性患者的 PK 特征与女性患者相似。本研究中开发的群体 PK 参数可用于模拟各种剂量方案下美罗培南的 PK 特征，以便精确计算%T > MIC。PK-PD 分析表明，0.5g 每 6 小时（q6h）比 1g 每 12 小时（q12h）更有效，尽管每天总共提供 2g。对于敏感性相对较低的病原体铜绿假单胞菌（MIC≥2μg/ml），美罗培南 1g 每 8 小时和/或更长的输注时间的剂量方案更好。尽管在少数患者中鉴定出了病原体，但 75%T > MIC（89%）的达标率与微生物学反应（89%）相当。在各种条件下进行的本 PK-PD 分析有助于发热性中性粒细胞减少症的治疗。
